This study was designed as a Phase II multi-centered, placebo- controlled, double-blind, 4-arm parallel trial to evaluate chimeric anti-TNF antibody (cA2) for RA. Patients who completed the 12 week study were offered a chance to enroll in a repeated-dose treatment extension study. In this study we evaluated the safety, tolerance, clinical response, and immunogenicity of repeated treatments with 10 mg/kg of cA2. PET scanning of both wrists was performed at baseline and 4 weeks after theapy to assess changes in wrist metabolism activity brought about by chimeric anti-TNF therapy. Twelve patients completed the single-dose study. Three of the twelve patients declined to enter the open-label extension. Seven patients have completed all treatment opportunities, and have shown a clinical response. One patient developed cellulitis in the infusion arm and was dropped from the study. Another patient dropped due to lack of efficacy. Significance: Tumor necrosis factor- (TNF- ) is a proinflammatory cytokine that is overexpressed in synovial tissue from patients with RA. Several lines of evidence from animal models of arthritis and from human studies in vitro and ex vivo suggest that TNF- plays a major role in stimulating joint inflammation. Further support for this hypothesis comes from previous clinical trial demonstrating that a single infusion of chimeric anti-TNF- decreases joint pain and swelling in patients with RA. Low dose, weekly methotrexate (MTX) therapy is widely viewed as the most effective therapy for patients with RA. However, many patients receiving MTX achieve only a partial therapeutic response. It is possible that in such patients periodic infusions of chimeric anti-TNF- in combination with MTX therapy would result in further clinical improvement without significant toxicity. Preliminary analysis of data from our study indicates that chimeric anti-TNF- can reduce the signs and symptoms of joint inflammation in patients with RA receiving MTX therapy. Previous studies have shown by positron emission tomography (PET) that swollen and tender joints from patients with RA demonstrate increased metabolic activity. The mechanism by which chimeric anti-TNF- reduces joint pain and swelling is presumed to be neutralization of TNF- inside the joint which in turn downregulates the inflammatory response. The metabolic activity in an inflamed joint most likely derives from the inflammatory cell population (e.g. granulocytes, lymphocytes). Thus, chimeric anti-TNF- would be expected to decrease metabolic activity if it decreased the recruitment of inflammatory cells to the joint or suppressed their activity. Our data using PET shows that chimeric anti- TNF- reduces joint metabolic activity in those patients with RA who achieved a therapeutic response. These results confirm the biological activity of chimeric anti-TNF- in patients with RA. Future plans: A phase III placebo-controlled clinical trial is planned to further evaluate the efficacy, tolerability, and safety of chimeric anti-TNF- in patients with RA receiving concomitant MTX therapy.